Tryptophan-substituted antimicrobial peptide temporin-1CEb: <i>in vitro</i> and <i>in vivo</i> antibacterial activity against clinically isolated multidrug-resistant <i>Klebsiella pneumonia</i>.
Tryptophan (Trp)-substituted antimicrobial peptides (AMPs) exhibit enhanced interactions with bacterial cell membranes, potentially improving their antimicrobial efficacy. Klebsiella pneumoniae (20.59% of 2054 ICU isolates) is resistant to multiple clinically used antibiotics and presents significant treatment challenges. In the present study, three Trp-modified peptides (I4W, L12W, and I1WL5W) are generated by substituting Ile or Leu residues in temporin-1CEb, a peptide derived from frog skin, with Trp at various sites to assess their antibacterial effects and mechanisms against K . pneumoniae . Compared with L12W, both I4W and I1WL5W display superior antimicrobial activity and lower cytotoxicity. Mechanistic studies reveal that AMPs exert antibacterial and bactericidal effects through bacterial surface charge neutralization, insertion into bacterial cell membranes, increase permeability of both the inner and outer membranes, and disruption of membrane integrity. Notably, I1WL5W exhibit the most potent membrane-disrupting activity. Assessment of the impact of Trp-containing peptides on bacterial biofilms reveals that these peptides not only inhibit exopolysaccharide production and biofilm formation but also degrade preformed biofilms. A murine lung infection model is established to investigate the therapeutic efficacy of I1WL5W against MDRKP 1203-induced lung infection in mice. Compared with the control treatment, treatment with I1WL5W results in reduced bacterial counts and levels of IL-6 and TNF-α in both the blood and lung tissues of MDRKP 1203-infected mice, and treatment with I1WL5W improves lung tissue structure. The present study provides valuable insights for designing Trp-containing peptides with potent antimicrobial properties by facilitating their penetration across bacterial membranes.
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